A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions. © 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.